Methods and compositions for modulating alpha adrenergic receptor activity

ABSTRACT

Methods and compositions for the treatment of pain using this area derivatives. Particularly disclosed are new compositions for the treatment of chronic pain, and methods for their use.

BACKGROUND OF THE INVENTION

Human adrenergic receptors are integral membrane proteins which havebeen classified into two broad classes, the alpha and the betaadrenergic receptors. Both types mediate the action of the peripheralsympathetic nervous system upon binding of catecholamines,norepinephrine and epinephrine.

Norepinephrine is produced by adrenergic nerve endings, whileepinephrine is produced by the adrenal medulla. The binding affinity ofadrenergic receptors for these compounds forms one basis of theclassification: alpha receptors tend to bind norepinephrine morestrongly than epinephrine and much more strongly than the syntheticcompound isoproterenol. The preferred binding affinity of these hormonesis reversed for the beta receptors. In many tissues, the functionalresponses, such as smooth muscle contraction, induced by alpha receptoractivation are opposed to responses induced by beta receptor binding.

Subsequently, the functional distinction between alpha and betareceptors was further highlighted and refined by the pharmacologicalcharacterization of these receptors from various animal and tissuesources. As a result, alpha and beta adrenergic receptors were furthersubdivided into α₁, α₂, β₁, and β₂ subtypes.

Functional differences between α₁ and α₂ receptors have been recognized,and compounds which exhibit selective binding between these two subtypeshave been developed. Thus, in WO 92/0073, the selective ability of theR(+) enantiomer of terazosin to selectively bind to adrenergic receptorsof the α₁ subtype was reported. The α₁/α₂ selectivity of this compoundwas disclosed as being significant because agonist stimulation of the α₂receptors was said to inhibit secretion of epinephrine andnorepinephrine, while antagonism of the α₂ receptor was said to increasesecretion of these hormones. Thus, the use of non-selectivealpha-adrenergic blockers, such as phenoxybenzamine and phentolamine,was said to be limited by their α₂adrenergic receptor mediated inductionof increased plasma catecholamine concentration and the attendantphysiological sequelae (increased heart rate and smooth musclecontraction).

For a general background on the α-adrenergic receptors, the reader'sattention is directed to Robert R. Ruffolo, Jr., α-Adrenoreceptors:Molecular Biology, Biochemistry and Pharmacology, (Progress in Basic andClinical Pharmacology series, Karger, 1991), wherein the basis of α₁/α₂subclassification, the molecular biology, signal transduction, agoniststructure-activity relationships, receptor functions, and therapeuticapplications for compounds exhibiting α-adrenergic receptor affinity wasexplored.

The cloning, sequencing and expression of alpha receptor subtypes fromanimal tissues has led to the subclassification of the α₁adrenoreceptors into α_(1A), α_(1B), and α_(1D). Similarly, the α₂adrenoreceptors have also been classified α_(2A), α_(2B), and α_(2C)receptors. Each α₂ receptor subtype appears to exhibit its ownpharmacological and tissue specificities. Compounds having a degree ofspecificity for one or more of these subtypes may be more specifictherapeutic agents for a given indication than an α₂ receptorpan-agonist (such as the drug clonidine) or a pan-antagonist.

Among other indications, such as the treatment of glaucoma,hypertension, sexual dysfunction, and depression, certain compoundshaving alpha 2 adrenergic receptor agonist activity are knownanalgesics. However, many compounds having such activity do not providethe activity and specificity desirable when treating disorders modulatedby alpha-2 adrenoreceptors. For example, many compounds found to beeffective agents in the treatment of pain are frequently found to haveundesirable side effects, such as causing hypotension and sedation atsystemically effective doses. There is a need for new drugs that providerelief from pain without causing these undesirable side effects.Additionally, there is a need for agents which display activity againstpain, particularly chronic pain, such as chronic neuropathic andvisceral pain.

British Patent 1 499 485, published February 1, 1978 describes certainthiocarbamide derivatives; some of these are said to be useful in thetreatment of conditions such as hypertension, depression or pain.

OBJECTS OF THE INVENTION

It is an object of the invention to provide compounds and compositionsuseful in treating disorders modulated by alpha-2 adrenoreceptors.

It is an object of this invention to provide novel compounds havingsubstantial analgesic activity in the treatment of chronic pain,regardless of origin. Chronic pain may be, without limitation, visceral,inflammatory or neuropathic in origin. Such chronic pain may arise as aresult of, or be attendant to, conditions including without limitation:arthritis, (including rheumatoid arthritis), spondylitis, goutyarthritis, osteoarthritis, juvenile arthritis, and autoimmune diseasesincluding, without limitation, lupus erythematosus.

These compositions can also be used within the context of the treatmentof chronic gastrointestinal inflammations, Crohn's disease, gastritis,irritable bowel disease (IBD) and ulcerative colitis; and in treatmentof visceral pain, including pain caused by cancer or attendant to thetreatment of cancer as, for example, by chemotherapy or radiationtherapy.

These compositions can be used within the context of the treatment ofother chronic pain symptoms, and especially in the treatment of chronicforms of neuropathic pain, in particular, without limitation, neuralgia,herpes, deafferentation pain, and diabetic neuropathies.

It is also an object of this invention to provide novel compounds fortreating ocular disorders, such as ocular hypertension, glaucoma,hyperemia, conjunctivitis and uveitis.

It is also an object of this invention to provide novel compounds fortreating the pain associated with substance abuse and/or withdrawal.

It is a still further object of this invention to provide such compoundswhich have good activity when delivered by peroral, parenteral,intranasal, ophthalmic, and/or topical dosing, or injection.

It is also an object of this invention to provide methods of treatingpain through the therapeutic administration of the compounds disclosedherein.

It is further an object of the present invention to provide methods oftreating conditions known to be susceptible to treatment through alpha 2adrenergic receptors.

SUMMARY OF THE INVENTION

The present invention is directed to compounds having the formula:

wherein R₁ is F or H, R₂ is Cl or H, and R₃ is F or H; and wherein if R₁is F then R₂ and R₃ are both H; and if R₁ is H then R₂ is Cl and R₃ isF, and alkyl esters thereof, and pharmaceutically acceptable salts ofthese compounds.

The invention is also directed to methods of treating pain, particularlychronic pain, through the administration of pharmaceutically effectiveamounts of compounds of the above structure.

Further, the invention is directed to methods of treating glaucomathrough the administration of a pharmaceutically effective amount ofthese compounds.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention is directed to compounds of Formula1:

wherein R₁ is F or H, R₂ is Cl or H, and R₃ is F or H; and wherein if R₁is F then R₂ and R₃ are both H; and if R₁ is H then R₂ is Cl and R₃ isF, and alkyl esters thereof, and pharmaceutically acceptable salts ofthese compounds.

Preferred compounds corresponding to this structure are the followingcompound (hereinafter termed Formula 2):

and the following compound (hereinafter termed Formula 3):

and their alkyl esters, and pharmaceutically acceptable derivativesand/or salts of these compounds.

Applicants have discovered that these compounds activate α₂ receptors,particularly α_(2B) receptors. Additionally, these compounds act as ahighly effective analgesic, particularly in chronic pain models, withminimal undesirable side effects, such as sedation and cardiovasculardepression, commonly seen with agonists of the α₂ receptors.

Such compounds may be administered at pharmaceutically effectivedosages. Such dosages are normally the minimum dose necessary to achievethe desired therapeutic effect; in the treatment of chromic pain, thisamount would be roughly that necessary to reduce the discomfort causedby the pain to tolerable levels. Generally, such doses will be in therange 1-1000 mg/day; more preferably in the range 10 to 500 mg/day.However, the actual amount of the compound to be administered in anygiven case will be determined by a physician taking into account therelevant circumstances, such as the severity of the pain, the age andweight of the patient, the patient's general physical condition, thecause of the pain, and the route of administration.

The compounds are useful in the treatment of pain in a mammal;particularly a human being. Preferably, the patient will be given thecompound orally in any acceptable form, such as a tablet, liquid,capsule, powder and the like. However, other routes may be desirable ornecessary, particularly if the patient suffers from nausea. Such otherroutes may include, without exception, transdermal, parenteral,subcutaneous, intranasal, intrathecal, intramuscular, intravenous, andintrarectal modes of delivery. Additionally, the formulations may bedesigned to delay release of the active compound over a given period oftime, or to carefully control the amount of drug released at a giventime during the course of therapy.

Another aspect of the invention is drawn to therapeutic compositionscomprising the compounds of Formula 1 and alkyl esters andpharmaceutically acceptable derivatives and/or salts of these compoundsand a pharmaceutically acceptable excipient. Such an excipient may be acarrier or a diluent; this is usually mixed with the active compound, orpermitted to dilute or enclose the active compound. If a diluent, thecarrier may be solid, semi-solid, or liquid material that acts as aexcipient or vehicle for the active compound. The formulations may alsoinclude wetting agents, emulsifying agents, preserving agents,sweetening agents, and/or flavoring agents. If used as in an ophthalmicor infusion format, the formulation will usually contain one or moresalt to influence the osmotic pressure of the formulation.

In another aspect, the invention is directed to methods for thetreatment of pain, particularly chronic pain, through the administrationof a compound of Formula 1, and pharmaceutically acceptable alkylesters, salts, and derivatives thereof to a mammal in need thereof. Asindicated above, the compound will usually be formulated in a formconsistent with the desired mode of delivery.

It is known that chronic pain (such as pain from cancer, arthritis, andmany neuropathic injuries) and acute pain (such as that pain produced byan immediate mechanical stimulus, such as tissue section, pinch, prick,or crush) are distinct neurological phenomena mediated to a large degreeeither by different nerve fibers and neuroreceptors or by arearrangement or alteration of the function of these nerves upon chronicstimulation. Sensation of acute pain is transmitted quite quickly,primarily by afferent nerve fibers termed C fibers, which normally havea high threshold for mechanical, thermal, and chemical stimulation.While the mechanisms of chronic pain are not completely understood,acute tissue injury can give rise within minutes or hours after theinitial stimulation to secondary symptoms, including a regionalreduction in the magnitude of the stimulus necessary to elicit a painresponse. This phenomenon, which typically occurs in a region emanatingfrom (but larger than) the site of the original stimulus, is termedhyperalgesia. The secondary response can give rise to profoundlyenhanced sensitivity to mechanical or thermal stimulus.

The A afferent fibers (Aβ and Aδ fibers) can be stimulated at a lowerthreshold than C fibers, and appear to be involved in the sensation ofchronic pain. For example, under normal conditions, low thresholdstimulation of these fibers (such as a light brush or tickling) is notpainful. However, under certain conditions such as those following nerveinjury or in the herpesvirus-mediated condition known as shingles theapplication of even such a light touch or the brush of clothing can bevery painful. This condition is termed allodynia and appears to bemediated at least in part by Aδ afferent nerves. C fibers may also beinvolved in the sensation of chronic pain, but if so it appears clearthat persistent firing of the neurons over time brings about some sortof change which now results in the sensation of chronic pain.

By “acute pain” is meant immediate, usually high threshold, pain broughtabout by injury such as a cut, crush, burn, or by chemical stimulationsuch as that experienced upon exposure to capsaicin, the activeingredient in chili peppers.

By “chronic pain” is meant pain other than acute pain, such as, withoutlimitation, neuropathic pain, visceral pain (including that broughtabout by Cron's disease and irritable bowel syndrome (IBS)), andreferred pain.

EXAMPLES Example 1

Synthesis of 1-(3-chloro-2-fluorobenzyl)-3-(2-hydroxyethyl)-thiourea(Formula 2)

One molar equivalent of 3-chloro-2-fluoro-benzyl bromide (commerciallyavailable from e.g., Lancaster Synthesis, Ltd.) is permitted to reactwith 2 molar equivalents of potassium isothiocyanate indimethylformamide (DMF) containing 0.5 molar equivalent of NaI at 90° C.for 5 hours with stirring to yield 3-chloro-2-fluorobenzylisothiocyanate. The reaction mixture is permitted to cool to roomtemperature, and the solution is diluted with H20 and extracted withether. The ether phase containing the product is removed and thereaction mixture extracted twice more with fresh ether. The ether phasesare combined and the product is concentrated in a Speed Vac® vacuumcentrifuge (using house vacuum) set in a water bath at about 45° C. Whenthe ether has evaporated, the unpurified 3-chloro-2-fluorobenzylisothiocyanate is a viscous liquid.

3.57 g of this compound is mixed with 3 molar equivalents ofethanolamine in acetonitrile, and a catalytic amount (less than 1%) ofDMAP (N-N-dimethyl amino pyridine) is added. The reaction mixture isincubated for 14 hours at room temperature with constant stirring. Theresulting solution is then concentrated using the Speed Vac® vacuumcentrifuge in a 60° C.−70° C. water bath.

The product, 1-(3-chloro-2-fluorobenzyl)-3-(2-hydroxyethyl)-thiourea, ispurified by liquid chromatography using 200-300 mesh silica gel in aglass column. The concentrated reaction solution is applied to thecolumn and the column washed with three column volumes of Solvent A (50%ethyl acetate/50% hexanes). The product is then eluted using 2-3 columnvolumes of Solvent B (10% methanol/90% ethyl acetate). The elutedproduct is again concentrated in a Speed Vac® vacuum centrifuge toremove the solvent. The product is then permitted to stand at roomtemperature, where is crystallizes spontaneously. The crystals arestored in the freezer at −78° C.

The product has the following spectroscopic characteristics: ¹H NMR (D₆DMSO, 300 MHz) δ7.98 (br s, 1 H), 7.63 (br s, 1 H), 7.46 (t, J=3.9 Hz, 1H), 7.32-7.18 (m, 2 H), 4.78 (br s, 1H), 4.72 (d, J=3.9 Hz, 2 H), 3.47(br s, 4 H).

In order to compare the biological activity of1-(3-chloro-2-fluorobenzyl)-3-(2-hydroxyethyl)-thiourea with that of the2-fluorobenzyl derivative (FORMULA 4) and the 4-flurobenzyl derivative(FORMULA 3), FORMULA 4 is synthesized using 2-fluoro-benzyl bromide(also commercially available) as the starting material. FORMULA 3 issynthesized using commercially purchased 4-fluorobenzyl isothiocyanate.Other synthetic steps are analogous to those used above to synthesizethe compound of FORMULA 2.

The 2-fluorobenzyl isothiourea derivative (hereinafter termed FORMULA 4)has the following formula:

The physiological activity of these compounds was tested using fourmodels: a rat locomotor model to assess sedation, an assay ofcardiovascular activity in monkeys, a rat thermal paw withdrawal assay(Dirig et al., J. Neurosci. Methods 76:183-191 (1997) to test thealleviation of acute pain, and the rat spinal nerve ligation allodyniamodel (Kim and Chung, Pain 50:355-363 (1992) to assess the alleviationof neuropathic pain and central sensitization typical of chronic pain.As is known to those of skill in the art, these tests are establishedpharmacological methods for determining chronic pain, respectively, ofpharmaceutical agents.

Example 2

Sedative Activity

To test sedation, six male Sprague-Dawley rats were given up to 3 mg/kgof each compound in a saline or DMSO vehicle by intraperitonealinjection (i.p.). Sedation was graded 30 minutes followingadministration of the drug by monitoring locomotor skills as follows.

The Sprague-Dawley rats are weighed and 1 ml/kg body weight of anappropriate concentration (ie. 3 mg/ml for a final dose of 3 mg/kg) drugsolution is injected intraperitoneally. FORMULA 3 is formulated inapproximately 10% DMSO and FORMULA 2 and FORMULA 4 are formulated in 50%DMSO. The results are compared to 29 historical controls that wereinjected with 1 ml/kg saline or 50% DMSO. Rat activity is thendetermined 30 minutes after injection of the drug solution. Rats areplaced in a dark covered chamber and a digicom analyzer (OmnitechElectronic) quantitates their exploratory behavior for a five-minuteperiod. The machine records each time the rat 30 interrupts an array of32 photoelectric beams in the X and Y orientation.

The results show that, in comparison to the appropriate vehiclecontrols, none of the compounds caused a statistically significantreduction in the exploratory activity of the rats. FORMULA 2 and FORMULA3 were tested at 1 mg/kg and FORMULA 4 was tested at 3 mg/kg. Thus, thecompounds are not sedating.

Example 3

Effects on Cardiovascular System

To test the effect of the compounds on the cardiovascular system, sixcynomolgus monkeys were given 500 μg/kg of each compound by intravenousinjection (i.v.). The effects of each compound on the animals' bloodpressure and heart rate was measured at time intervals from 30 minutesto six hours following administration of the drug. The peak change froma baseline measurement taken 30 minutes before drug administration isrecorded using a blood pressure cuff modified for use on monkeys.

The monkeys are weighed (approximately 4 kg) and an appropriate volume(0.1 ml/kg) of a 5 mg/ml solution of each compound formulated in 10%DMSO is injected into the cephalic vein in the animals' arms.Cardiovascular measurements are made with a BP 100S automatedsphygmomanometer (Nippon Colin, Japan) at 0.5, 1, 2, 4 and 6 hours.

The results show that, in comparison to the predrug control, none of thecompounds have any detectable effect on the cardiovascular system.

Example 4

Alleviation of Acute Pain

Models to measure sensitivity to acute pain have typically involved theacute application of thermal stimuli; such a stimulus causes aprogrammed escape mechanism to remove the affected area from thestimulus. The proper stimulus is thought to involve the activation ofhigh threshold thermoreceptors and C fiber dorsal root ganglion neuronsthat transmit the pain signal to the spinal cord.

The escape response may be “wired” to occur solely through spinalneurons, which receive the afferent input from the stimulated nervereceptors and cause the “escape” neuromuscular response, or may beprocessed supraspinally—that is, at the level of the brain. A commonlyused method to measure nociceptive reflexes involves quantification ofthe withdrawal or licking of the rodent paw following thermalexcitation. See Dirig, D. M. et al., J. Neurosci. Methods 76:183-191(1997) and Hargreaves, K. et al., Pain 32:77-88 (1988), herebyincorporated by reference herein.

In a variation of this latter model, male Sprague-Dawley rats weretested by being placed on a commercially available thermal stimulusdevice constructed as described in Hargreaves et al. This deviceconsists of a box containing a glass plate. The nociceptive stimulus isprovided by a focused projection bulb that is movable, permitting thestimulus to be applied to the heel of one or both hindpaws of the testanimal. A timer is actuated with the light source, and the responselatency (defined as the time period between application of the stimulusand an abrupt withdrawal of the hindpaw) is registered by use of aphotodiode motion sensor array that turns off the timer and light.Stimulus strength can be controlled by current regulation to the lightsource. Heating is automatically terminated after 20 seconds to preventtissue damage.

Four test animals per group were weighed (approximately 0.3 kg) andinjected intraperitonealy (i.p.) with 1 ml/kg of each compoundformulated in approximately 50% dimethylsulfoxide (DMSO) vehicle.Animals received a 0.3 mg/kg and a 3 mg/kg dose of the three compounds.Rats were acclimated to the test chamber for about 15 minutes prior totesting. The paw withdrawal latency was measured at 30, 60 and 120minutes after drug administration. The right and left paws were tested 1minute apart, and the response latencies for each paw were averaged.Stimulus intensity was sufficient to provide a temperature of 45-50degrees centigrade to each rat hindpaw.

The results show that none of the compounds provide analgesic effects inthis bioassay of acute pain. The response latencies for rats treatedwith the compounds were not statistically different from the responselatencies of the rats treated with vehicle alone.

Example 5

Alleviation of Chronic Pain

A model for chronic pain (in particular peripheral neuropathy such ascausalgia) involves the surgical ligation of the L5 (and optionally theL6) spinal nerves on one side in experimental animals. Rats recoveringfrom the surgery gain weight and display a level of general activitysimilar to that of normal rats. However, these rats developabnormalities of the foot, wherein the hindpaw is moderately exerted andthe toes are held together. More importantly, the hindpaw on the sideaffected by the surgery appears to become sensitive to pain fromlow-threshold mechanical stimuli, such as that producing a faintsensation of touch in a human, within about 1 week following surgery.This sensitivity to normally non-painful touch is called “tactileallodynia” and lasts for at least two months. The response includeslifting the affected hindpaw to escape from the stimulus, licking thepaw and holding it in the air for many seconds. None of these responsesis normally seen in the control group.

Rats are anesthetized before surgery. The surgical site is shaved andprepared either with betadine or Novacaine. Incision is made from thethoracic vertebra Xlll down toward the sacrum. Muscle tissue isseparated from the spinal vertebra (left side) at the L4-S2 levels. TheL6 vertebra is located and the transverse process is carefully removedwith a small rongeur to expose the L4-L6 spinal nerves. The L5 and L6spinal nerves are isolated and tightly ligated with 6-0 silk thread. Thesame procedure is done on the right side as a control, except noligation of the spinal nerves is performed.

A complete hemostasis is confirmed, then the wounds are sutured. A smallamount of antibiotic ointment is applied to the incised area, and therat is transferred to the recovery plastic cage under a regulatedheat-temperature lamp. On the day of the experiment, at least seven daysafter the surgery, six rats per test group are administered the testdrugs by intraperitoneal (i.p.) injection or oral gavage. For i.p.injection, the compounds are formulated in approximately 50% DMSO andgiven in a volume of 1 ml/kg body weight. FORMULA 2 was tested at dosesranging between 1 and 300 μg/kg, FORMULA 3 was tested at doses between0.1 and 3 mg/kg and FORMULA 4 was tested at doses of 0.3 and 3 mg/kg.FORMULA 2 was also administered by oral gavage at doses of 0.1, 0.3 and1 mg/kg body weight to 24-hour fasted rats. A volume equal to 1 ml/kgbody weight of an appropriate concentration (ie. 1 mg/ml for a 1 mg/kgdose) of FORMULA 2 formulated in approximately 50% DMSO was injectedusing an 18-gauge, 3-inch gavage needle that is slowly inserted throughthe esophagus into the stomach.

Tactile allodynia is measured prior to and 30 minutes after drugadministration using von Frey hairs that are a series of fine hairs withincremental differences in stiffness. Rats are placed in a plastic cagewith a wire mesh bottom and allowed to acclimate for approximately 30minutes. The von Frey hairs are applied perpendicularly through the meshto the mid-plantar region of the rats' hindpaw with sufficient force tocause slight buckling and held for 6-8 seconds. The applied force hasbeen calculated to range from 0.41 to 15.1 grams. If the paw is sharplywithdrawn, it is considered a positive response. A normal animal willnot respond to stimuli in this range, but a surgically ligated paw willbe withdrawn in response to a 1-2 gram hair. The 50% paw withdrawalthreshold is determined using the method of Dixon, W. J., Ann. Rev.Pharmacol. Toxicol. 20:441-462 (1980). The post-drug threshold iscompared to the pre-drug threshold and the percent reversal of tactilesensitivity is calculated based on a normal threshold of 15.1 grams.

The results showed that FORMULA 4 had no analgesic activity at doses upto 3 mg/kg. Surprisingly, AGN 196204 and FORMULA 2 were both able toreduce the response to the tactile stimuli that indicate tactileallodynia. FORMULA 3 reversed the allodynic pain by 34% at an i.p. doseof 0.3 mg/kg, 32% at 1 mg/kg and 26% at 3 mg/kg. FORMULA 2 reversed theallodynia by 55% at an i.p. dose of 3 μg/kg, 85% at 10 μg/kg, 90% at 30μg/kg, 95% at 100 μg/kg and 92% at 300 μg/kg. The oral doses of FORMULA2 ranging from 0.1 to 1 mg/kg alleviated the allodynic pain by 82-86%.Thus, FORMULA 3 and FORMULA 2 are analgesic in a model of chronic pain.

Example 6

Treatment of Allodynia with FORMULA 3

A 50 year old male in generally good physical condition suffers fromserious pain to his upper body due caused by contact of his skin withhis clothing. The patient is unable to wear clothing on his upper bodywithout severe pain. His symptoms suggest a diagnosis of shingles.

The patient is given a therapeutically effective oral dose of FORMULA 3in capsule form as needed for the treatment of pain. Following two day'streatment, the patient reports that the allodynia resulting fromshingles is markedly reduced, and that he is able to wear clothing onhis upper body with greater comfort.

Example 6

Treatment of Allodynia with FORMULA 2

Same facts as in Example 5, except the patient is given atherapeutically effective oral dose of FORMULA 2 in capsule form asneeded for the treatment of pain. Following two day's treatment, thepatient reports that the allodynia resulting from shingles is markedlyreduced, and that he is able to wear clothing on his upper body withgreater comfort.

Example 7

Treatment of Visceral Pain with FORMULA 3

A 43 year old female patient suffering from colon cancer and undergoingchemotherapy experiences severe visceral pain associated with thisprimary condition. Treatment of this pain with opiates have beenineffective to provide substantial relief.

The patient is given a therapeutic amount of FORMULA 3 by intravenousinfusion in a pharmaceutically acceptable vehicle. The treatment isgiven twice daily. After two days the patient reports a significantalleviation in the visceral pain associated with her condition.

Example 8

Treatment of Visceral Pain with FORMULA 2

Under the same facts as Example 7, except the patient is given FORMULA 2instead of FORMULA 3. After two days the patient reports a significantalleviation in the visceral pain associated with her condition.

The examples contained herein are intended to be exemplary only, and donot limit the scope of the invention, which is defined by the claimsthat conclude this specification.

We claim:
 1. A method of treating pain in a mammal in need thereofcomprising the step: administering to said patient a therapeuticallyeffective dose of a composition comprising a compound represented by theformula:

wherein R₁ is F or H, R₂ is Cl or H, and R₃ is F or H; and wherein if R₁is F then R₂ and R₃ are both H; and if R₁ is H then R₂ is Cl and R₃ isF, and pharmaceutically acceptable salts of these compounds.
 2. Themethod of claim 1 wherein said compound is represented by the formula

and alkyl esters thereof, and pharmaceutically acceptable salts of thesecompounds.
 3. The method of claim 2 wherein said compound isadministered orally.
 4. The method of claim 1 wherein said compound isrepresented by the formula

and pharmaceutically acceptable salts of these compounds.
 5. The methodof claim 4 wherein said compound is administered orally.
 6. The methodof claim 1 wherein said pain is chronic pain.
 7. The method of claim 1wherein said pain is neuropathic pain.
 8. The method of claim 1 whereinsaid pain is visceral pain.
 9. The method of claim 1 wherein said painis referred pain.
 10. The method of claim 1 wherein said pain isallodynic pain.